A seven-membered indole spiroheterocyclic chiral derivative constructed by palladium catalysis

Abstract

The present invention relates to the technical field of pharmaceutical chemistry, discloses a seven-membered indole spiro heterocyclic chiral derivative constructed by palladium catalysis, and provides a preparation method of the chiral derivative, prepares the seven-membered indole spiro heterocyclic chiral derivative by intermolecular reaction, and the preparation method is simple to operate, has high reaction universality, high yield and good enantioselectivity. The seven-membered indole spiro heterocyclic chiral derivative constructed by palladium catalysis provided by the present invention can undergo double bond epoxidation reaction to generate double bond epoxidation products, and the seven-membered indole spiro heterocyclic chiral derivative and its double bond epoxidation product have excellent antibacterial activity and have broad market application prospects.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, in particular to a seven-membered indole spiro heterocyclic chiral derivative. Background Art

[0002] Spiro compounds are a class of polycyclic compounds, in which at least two rings in the molecule share a carbon atom. A few compounds also share other atoms such as silicon, phosphorus, and arsenic. Spiro compounds have a rigid structure in which the two ring planes are perpendicular to each other. Due to the unique structure and properties of spiro compounds, their applications in asymmetric catalysis, luminescent materials, photochromic materials, medicines, pesticides, polymer adhesives, etc. have attracted more and more attention in recent years. In particular, the pharmacological activities of spiro compounds, such as anti-tumor, anti-anxiety, anti-inflammatory, antihypertensive, antipyretic and analgesic, have attracted the attention of more and more synthetic chemists and medicinal chemists. Heterocyclic spiro compounds contain highly electronegative heteroatoms such as oxygen and nitrogen, and have large intermolecular forces with other molecules, making them good chiral catalysts and stationary phase skeletons. Heterocyclic spiro compounds may also have special properties that are not possessed by general organic compounds, such as spiro conjugation, spiro hyperconjugation or anomeric effect. They are present in large quantities in natural products with biological activity and appear as the core skeleton of various important pharmaceutical active molecules. Among them, the indole spiro heterocyclic skeleton with a chiral center is a key component of drug molecules. Due to its high biological activity, it has attracted the research interest of more and more synthetic chemists and medicinal chemists in recent years. Studies have shown that there are few reports on the synthesis of chiral indole spiro heterocyclic skeletons through intermolecular reactions. Therefore, the development of new methods for indole spiro heterocyclic chiral compounds is still of great strategic significance. Summary of the invention

[0003] In view of the problems in the prior art, the present invention provides a seven-membered indole spiroheterocyclic chiral derivative constructed by palladium catalysis, and a preparation method and use thereof.

[0004] The technical solution adopted by the present invention to solve the technical problem is: a seven-membered indole spiroheterocyclic chiral derivative constructed by palladium catalysis, the general formula of the chiral derivative is:

[0005]

[0006] Among them, R 1 is one of phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, naphthyl, and heterocyclic group;

[0007] R 2 is one of phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, naphthyl, and heterocyclic group;

[0008] Preferably, the optional structures of the chiral derivative include but are not limited to:

[0009]

[0010] Furthermore, the present invention also provides a method for preparing a seven-membered indole spiroheterocyclic chiral derivative constructed by palladium catalysis, the method comprising the following steps: adding 5 mol% eqPd2(dba)3 to a 25 mL sealed tube dried in a glove box; . CHCl3 (and 15 mol% eq chiral ligand L2 (, the lid is sealed, taken out of the glove box, 2 mL of dry mesitylene is added under argon atmosphere, and the resulting suspension is stirred at 60° C. for 30 minutes for coordination, and then the reactant is cooled to room temperature, 1.0 eq of azadiene substrate 1 and 2.0 eq of vinyl cyclic carbonate substrate 2 are added under argon atmosphere, the reaction mixture is stirred at room temperature for 2 hours, and then it is transferred to 100° C. and stirred for 3 hours, the reaction is completed by monitoring by thin layer chromatography, and then the reaction mixture is directly purified by column chromatography to obtain the target product 3, which is the chiral derivative, and the reaction formula is:

[0011]

[0012] Furthermore, the present invention provides R 1 The preparation method of the azadiene substrate 1a having a phenyl group comprises the following steps:

[0013] Step 1: Weigh 9.53 g of indole into a round-bottom flask, add 10.85 mL of TsN3, react at 60 °C for 14 h under condensation reflux conditions, the color changes to a dark red-brown liquid accompanied by solids, add a small amount of anhydrous methanol and stir until solids precipitate, filter and dry, and weigh to obtain a pink solid I;

[0014] Step 2: Weigh 1.2 g of I into a washed round-bottom flask covered with a rubber stopper, add 4 mL of dry DCM, 0.65 mL of benzaldehyde, and 1.3 mL of BF3·Et2O in sequence under argon, react at room temperature under argon atmosphere, and turn into a yellow solid after 1 h. Add a small amount of anhydrous methanol and sonicate until solid particles precipitate, filter and dry to obtain a light yellow solid II;

[0015] Step 3: Weigh 0.1eq Pd(OAc)2 and 0.15eq ligand L1 and add them to a sealed tube, add 10mL dry dichloromethane under argon atmosphere, react at 40°C for 30min, and the coordination is successful when the color changes from red to yellow; then add 1eq II, 3eq allyl bromide, and 2eq potassium tert-butoxide to the sealed tube under argon atmosphere, react at 40°C for 2h, monitor the reaction with thin layer chromatography, use petroleum ether / ethyl acetate system as the developing solvent, and the ratio of petroleum ether to ethyl acetate is 6:1. After the reaction is completed, concentrate and dry under reduced pressure, purify by column chromatography, use petroleum ether:ethyl acetate = 10:1 as the eluent, and 300mL of dichloromethane to obtain the azadiene substrate 1a;

[0016] The reaction formula for preparing azadiene substrate 1a is:

[0017]

[0018] Further, when the seven-membered indole spiroheterocyclic chiral derivative of the present invention is the structure shown in 3a above, its double bond epoxidation product can be prepared by double bond epoxidation reaction. Further, the preparation method of the double bond epoxidation product is specifically as follows: m-CPBA is added to the dichloromethane solution of 3a at room temperature, the reaction mixture is stirred at room temperature for 12 hours, and the reaction is monitored by thin layer chromatography. After the reaction is completed, the reaction is quenched with a saturated NaHCO3 solution and extracted with dichloromethane, the combined organic phase is collected and dried with anhydrous Na2SO4, and concentrated under reduced pressure. The residue is purified by silica gel chromatography, and petroleum ether / ethyl acetate is used for purification = 30 / 1-10 / 1. The product 4 is purified and separated, which is the double bond epoxidation product, and the double bond epoxidation reaction formula is:

[0019]

[0020] Furthermore, a seven-membered indole spiroheterocyclic chiral derivative constructed by palladium catalysis or the double bond epoxidation product has antibacterial effect and can be used for antibacterial purposes.

[0021] The present invention provides a seven-membered indole spiroheterocyclic chiral derivative synthesized by intermolecular reaction and constructed by palladium catalysis, and a method for preparing the chiral derivative, the chiral derivative has good antibacterial effect, and the preparation method is simple, the reaction is universal, the yield is high, and the enantioselectivity is good, and it has broad market application prospects. In addition, the present invention also provides a method for preparing a double bond epoxidation product of the chiral derivative, and the double bond epoxidation product also has an antibacterial effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is the single crystal structure of the product of Example 5. DETAILED DESCRIPTION

[0023] In order to make the technical means, creative features, objectives and effects of the present invention easy to understand, the present invention is further described below in conjunction with specific embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention.

[0024] Unless otherwise specified, the reagents and testing equipment used in the present invention are conventional commercially available reagents and equipment.

[0025] A seven-membered indole spiroheterocyclic chiral derivative constructed by palladium catalysis, wherein the chiral derivative has the general structural formula:

[0026]

[0027] Among them, R 1 is one of phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, naphthyl, and heterocyclic group;

[0028] R 2 It is one of phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, naphthyl and heterocyclic group.

[0029] The optional structures of the chiral derivatives include but are not limited to:

[0030]

[0031] A method for preparing a seven-membered indole spiroheterocyclic chiral derivative constructed by palladium catalysis comprises the following steps: adding 5 mol% eqPd2(dba)3 to a 25 mL sealed tube dried in a glove box; . CHCl3 (and 15 mol% eq chiral ligand L2 (, the lid is sealed, taken out from the glove box, 2 mL of dry mesitylene is added under argon atmosphere, and the resulting suspension is stirred at 60° C. for 30 minutes for coordination, and then the reactant is cooled to room temperature, 1.0 eq of azadiene substrate 1 and 2.0 eq of vinyl cyclic carbonate substrate 2 are added under argon atmosphere, the reaction mixture is stirred at room temperature for 2 hours, and then it is transferred to 100° C. and stirred for 3 hours, the reaction is completed by monitoring by thin layer chromatography, and then the reaction mixture is directly purified by column chromatography to obtain the corresponding target product 3, which is the chiral derivative, and the reaction formula is:

[0032]

[0033] Example 1

[0034] The seven-membered indole spiroheterocyclic chiral derivative of this embodiment is N-((2'R, 3S, Z)-1-allyl-2', 6'-diphenyl-4', 7'-dihydro-2'H-spiro[indole-3, 3'-oxacyclohexane]-2-ethylidene)-4-methylbenzenesulfonamide (carbonate is used when synthesizing the substrate)

[0035]

[0036] White solid, yield 85%, er 96:4, dr>95:5;

[0037] 1 H NMR (600MHz, CDCl3) δ (ppm): 7.97 (d, J = 8.4Hz, 2H), 7.76 (d, J = 7.2Hz, 1H), 7.48–7.46 (m, 2H), 7.42–7.40 (m, 2H), 7.35–7.32 (m, 3H),7.22(t,J=6.6Hz,1H),7.09-7.04(m,2H),6.98–6.95(m,2H),6.90(d,J=7.8Hz,2H),6.60(d,J=8.4Hz,1H),6.18–6.16(m,1 H),6.09(s,1H),5.17–5.11(m,1H),5.06(d,J=13.8Hz,1H),4.98(d,J=14.4Hz,1H),4.88(d,J=10.2Hz,1H),4.53(d,J=17.4Hz, 1H), 4.46–4.43 (m, 1H), 4.12 (dd, J=15.0, 4.2Hz, 1H), 4.00 (dd, J=16.2, 5.4Hz, 1H), 2.70 (dd, J=15.0, 8.4Hz, 1H), 2.45 (s, 3H).

[0038] 13 C NMR (151MHz, CDCl3) δ (ppm): 167.5, 144.6, 142.5, 142.2, 141.21, 141.16, 138.2, 131.0, 129.9, 129.3, 128.6, 128.2, 127.8,127.7,127.4,127.3,127.0,126.9,126.15,126.08,123.2,117.8,109.5,87.9,73.5,58.7,45.1,34.1,21.5.

[0039] This embodiment provides R 1 The preparation method of the azadiene substrate 1a having a phenyl group comprises the following steps:

[0040] Step 1: Weigh 9.53 g of indole into a round-bottom flask, add 10.85 mL of TsN3, react at 60 °C for 14 h under condensation reflux conditions, the color changes to a dark red-brown liquid accompanied by solids, add a small amount of anhydrous methanol and stir until solids precipitate, filter and dry, and weigh to obtain a pink solid I;

[0041] Step 2: Weigh 1.2 g of I and add it to a washed round-bottom flask covered with a rubber stopper. Under argon conditions, add 4 mL of dry dichloromethane, 0.65 mL of benzaldehyde, and 1.3 mL of BF3·Et2O in sequence. React at room temperature under argon atmosphere. After 1 h, it turns into a yellow solid. Add a small amount of anhydrous methanol and sonicate until solid particles precipitate. Filter and dry to obtain a light yellow solid II.

[0042] Step 3: Weigh 0.1eq Pd(OAc)2 and 0.15eq ligand L1 into a sealed tube, add 10mL dry dichloromethane under argon atmosphere, react at 40°C for 30min, and the coordination is successful when the color changes from red to yellow; then add 1eq II, 3eq allyl bromide, and 2eq potassium tert-butoxide into the sealed tube under argon atmosphere, react at 40°C for 2h, monitor the reaction with thin layer chromatography, use petroleum ether / ethyl acetate system as the developing solvent, and the ratio of petroleum ether to ethyl acetate is 6:1. After the reaction is completed, concentrate and dry under reduced pressure, purify by column chromatography, use petroleum ether:ethyl acetate = 10:1 as the eluent, and use 300mL dichloromethane to obtain the azadiene substrate 1a;

[0043] The reaction formula for preparing azadiene substrate 1a is:

[0044]

[0045] Example 2

[0046] The chiral derivative of the seven-membered indole spiroheterocyclic ring in this embodiment is N-((2'R, 3S, Z)-1-allyl-2'-(4-chlorophenyl)-6'-phenyl-4', 7'-dihydro-2'-hydrospiro[indole-3,3'-oxacyclohexane]-2-ethylidene)-4-methylbenzenesulfonamide (carbonate and 4-chloroindole are used in the synthesis of the substrate (indole is used in all other embodiments not described here))

[0047]

[0048] White solid, yield 91%, er 90:10, dr>95:5;

[0049] 1H NMR (600MHz, CDCl3) δ (ppm): 7.95 (d, J = 8.4Hz, 2H), 7.73 (d, J = 7.2Hz, 1H), 7.46 (d, J = 7.8Hz, 2H), 7.42–7.39 (m, 2H), 7.35–7 .32(m,3H),7.23(t,J=7.8Hz,1H),7.07(t,J=7.2Hz,1H),6.94(d,J=8.4Hz,2H),6.86(d,J=8.4Hz,2H),6.64(d,J=7.8Hz,1H) ,6.17–6.15(m,1H),6.09(s,1H),5.25–5.18(m,1H),5.06–5.03(m,1H),4.98–4.94(m,2H),4.59(d,J=17.4Hz,1H),4.43(dd ,J=16.2,5.4Hz,1H),4.14(dd,J=15.6,4.8Hz,1H),4.02(dd,J=16.8,6.0Hz,1H),2.68(dd,J=15.6,9.0Hz,1H),2.45(s,3H).

[0050] 13 C NMR (151MHz, CDCl3) δ (ppm): 167.2, 144.6, 142.4, 142.3, 141.1, 141.0, 136.8, 133.5, 130.6, 129.6, 129.3, 128.7, 128.6,128.4,127.8,127.5,127.3,126.8,126.1,126.0,123.3,118.0,109.5,87.0,73.5,58.6,45.0,34.1,21.5.

[0051] Example 3

[0052] The chiral derivative of the seven-membered indole spiroheterocyclic ring in this embodiment is N-((2'R, 3S, Z)-1-allyl-6'-phenyl-2'-(p-tolyl)-4',7'-dihydro-2'-hydrospiro[indole-3,3'-oxacyclopropane]-2-ethylidene)-4-methylbenzenesulfonamide (carbonate and 4-methylindole are used in the synthesis of the substrate (indole is used in the other embodiments not described here))

[0053]

[0054] White solid, yield 87%, er 96:4, dr>95:5;

[0055] 1H NMR (600MHz, CDCl3) δ (ppm): 7.96 (d, J = 8.4Hz, 2H), 7.75 (d, J = 7.2Hz, 1H), 7.46 (d, J = 7.2Hz, 2H), 7.41–7.38 (m, 2H), 7. 33–7.31(m,3H),7.22(t,J=6.6Hz,1H),7.07(t,J=7.8Hz,1H),6.77(s,4H),6.61(d,J=8.4Hz,1H),6.17–6.15(m,1H),6 .03(s,1H),5.18–5.12(m,1H),5.04(d,J=14.4Hz,1H),4.95(d,J=15.6Hz,1H),4.85(d,J=10.2Hz,1H),4.49–4.45(m,2 H),4.10(dd,J=15.0,4.2Hz,1H),3.99(dd,J=15.6,5.4Hz,1H),2.68(dd,J=15.0,7.8Hz,1H),2.44(s,3H),2.15(s,3H).

[0056] 13 C NMR (151MHz, CDCl3) δ (ppm): 167.5, 144.6, 142.6, 142.1, 141.3, 141.2, 137.3, 135.4, 131.1, 129.9, 129.2, 128.6, 128 .1,127.9,127.8,127.4,126.90,126.88,126.1,126.0,123.1,117.4,109.4,87.9,73.5,58.7,45.0,34.2,21.5,20.9.

[0057] Example 4

[0058] The chiral derivative of the seven-membered indole spiroheterocyclic ring in this embodiment is N-((2'R, 3S, Z)-1-allyl-2'-(3-chlorophenyl)-6'-phenyl-4', 7'-dihydro-2'-hydrospiro[indole-3,3'-oxacyclohexane]-2-ethylidene)-4-methylbenzenesulfonamide (carbonate and 3-chloroindole are used in the synthesis of the substrate (indole is used in all other embodiments not described here))

[0059]

[0060] White solid, yield 51%, er 99:1, dr>95:5;

[0061] 1H NMR(600MHz, CDCl3)δ(ppm):7.97(d,J=7.8Hz,2H),7.74(d,J=7.2Hz,1H),7.46(d,J=7.8Hz,2H),7.42–7.40(m,2H),7.35–7.32( m,3H),7.25–7.22(m,1H),7.08(t,J=7.8Hz,1H),7.02(d,J=8.4Hz,1H),6.98(s,1H),6.88(t,J=7.8Hz,1H),6.76(d,J=7.8Hz,1H ),6.64(d,J=8.4Hz,1H),6.17–6.15(m,2H),5.22–5.16(m,1H),5.05(d,J=15.6Hz,1H),4.99–4.94(m,2H),4.65(d,J=16.8Hz,1H ), 4.41(dd,J=16.8,4.8Hz,1H), 4.16(d,J=15.0Hz,1H), 3.98(dd,J=16.2,6.0Hz,1H), 2.72(dd,J=14.4,8.4Hz,1H), 2.45(s,3H).

[0062] 13 C NMR (151MHz, CDCl3) δ (ppm): 167.3, 144.6, 142.4, 142.3, 141.0, 140.3, 133.1, 130.6, 129.7, 129.3, 128.7, 128.4, 1 27.8,127.6,127.5,127.3,126.8,126.15,126.06,125.0,123.3,118.2,109.4,86.7,73.5,58.6,45.0,34.1,21.5.

[0063] Example 5

[0064] The seven-membered indole spiroheterocyclic chiral derivative of this embodiment is N-((2'R, 3S, Z)-1-allyl-2'-(3-methoxyphenyl)-6'-phenyl-4', 7'-dihydro-2'-hydrospiro[indole-3,3'-oxacyclohexane]-2-ethylidene)-4-methylbenzenesulfonamide (carbonate and 3-methoxyindole are used in the synthesis of the substrate (the remaining embodiments not described here all use indole)).

[0065]

[0066] White solid, yield 81%, er 98:2, dr>95:5;

[0067] 1H NMR (600MHz, CDCl3) δ (ppm): 7.97 (d, J = 8.4Hz, 2H), 7.77 (d, J = 7.8Hz, 1H), 7.48 (d, J = 7.2Hz, 2H), 7.43–7.40 (m, 2H), 7.35–7.31 (m ,3H),7.23(t,J=7.2Hz,1H),7.09(t,J=7.2Hz,1H),6.89(t,J=7.2Hz,1H),6.64–6.59(m,3H),6.38(s,1H),6.19–6.17(m,1H),6.1 1(s,1H),5.21–5.15(m,1H),5.07(d,J=15.6Hz,1H),4.99(d,J=15.0Hz,1H),4.91(d,J=10.2Hz,1H),4.58(d,J=17.4Hz,1H),4.47 –4.44(m,1H),4.16(dd,J=15.0,4.2Hz,1H),4.01(dd,J=16.2,5.4Hz,1H),3.41(s,3H),2.71(dd,J=15.0,9.0Hz,1H),2.45(s,3H).

[0068] 13 C NMR (151MHz, CDCl3) δ (ppm): 167.5, 158.6, 144.6, 142.6, 142.2, 141.23, 141.15, 139.6, 131.2, 129.9, 129.2, 128.6, 128. 2,127.8,127.4,126.9,126.2,126.1,123.1,119.5,117.9,115.1,110.9,109.5,87.7,73.5,58.7,54.9,45.0,34.1,21.5.

[0069] Single crystal data of the product of Example 5 (see Figure 1 and the table below):

[0070]

[0071]

[0072] Example 6

[0073] The chiral derivative of the seven-membered indole spiroheterocyclic ring in this embodiment is N-((2'S, 3S, Z)-1-allyl-2'-(2-fluorophenyl)-6'-phenyl-4'-, 7'-dihydro-2'-hydrospiro[indole-3,3'-oxacyclohexane]-2-ethylidene)-4-methylbenzenesulfonamide (carbonate and 2-fluoroindole are used in the synthesis of the substrate (indole is used in all other embodiments not described here))

[0074]

[0075] White solid, yield 72%, er 92:8, dr>95:5;

[0076] 1 H NMR (600MHz, CDCl3) δ (ppm): 7.98 (d, J = 8.4Hz, 2H), 7.72 (d, J = 7.8Hz, 1H), 7.42 (d, J = 7.2Hz, 2H), 7.40–7.37 (m, 2H), 7.33–7.31 (m, 1H) ,7.29(d,J=7.8Hz,2H),7.23(t,J=7.2Hz,1H),7.08–7.02(m,2H),6.85(t,J=9.0Hz,1H),6.65(d,J=8.4Hz,1H),6.62(t,J=6.6Hz,1H), 6.45(t,J=7.8Hz,1H),6.22(s,1H),6.19–6.17(m,1H),5.31–5.24(m,1H),5.03(d,J=15.6Hz,1H),4.97(d,J=15.6Hz,1H),4.93(d,J=1 0.8Hz,1H),4.69–4.63(m,2H),4.13(dd,J=16.2,6.0Hz,1H),3.94(dd,J=15.6,4.8Hz,1H),2.76(dd,J=15.0,8.4Hz,1H),2.44(s,3H).

[0077] 13 C NMR (151MHz, CDCl3) δ (ppm): 166.2, 158.9 (C–F, 1 J C–F =248.7Hz),144.1,143.0,142.1,141.1,140.9,130.9,130.3,129.2(C–F, 3 J C–F =8.6Hz),129.1,129.03,129.01,128.6,128.4,127.4,126.7,126.4,126.0,125.5(C–F,2 J C–F =13.0Hz),123.2,122.9(C–F, 3 J C–F =2.9Hz),117.9,114.9(C–F, 2 J C–F =23.1Hz),109.6,81.2,73.7,58.2,45.8,34.5,21.5.

[0078] Example 7

[0079] The chiral derivative of the seven-membered indole spiroheterocyclic ring in this embodiment is N-((2'S, 3S, Z)-1-allyl-6'-phenyl-2'-(thiophen-2-yl)-4', 7'-dihydro-2'-hydrospiro[indole-3,3'-oxacyclohexane]-2-ethylidene)-4-methylbenzenesulfonamide (carbonate and thiophen-2-yl indole are used in the synthesis of the substrate (indole is used in all other embodiments not described here))

[0080]

[0081] White solid, yield 51%, er 91:9, dr>95:5;

[0082] 1 H NMR (600MHz, CDCl3) δ (ppm): 7.94 (d, J = 7.2Hz, 2H), 7.73 (d, J = 7.8Hz, 1H), 7.45 (d, J = 7.2Hz, 2H), 7.41–7.39 (m, 2H), 7.34– 7.27(m,4H),7.09(t,J=7.8Hz,1H),6.96(d,J=4.8Hz,1H),6.86(d,J=2.4Hz,1H),6.72–6.71(m,2H),6.49(s,1H),6.14–6.1 2(m,1H),5.33–5.27(m,1H),5.06(d,J=15.0Hz,1H),4.98(d,J=15.6Hz,1H),4.95(d,J=10.2Hz,1H),4.62(d,J=17.4Hz,1H) ,4.52–4.49(m,1H),4.17(dd,J=15.0,4.2Hz,1H),4.08(dd,J=16.8,6.0Hz,1H),2.64(dd,J=15.6,9.0Hz,1H),2.44(s,3H).

[0083] 13C NMR (151MHz, CDCl3) δ (ppm): 167.2, 144.7, 142.9, 142.2, 141.13, 141.08, 140.6, 131.0, 129.9, 129.2, 128.64, 128.5 5,128.1,127.5,126.8,126.2,126.1,125.7,125.4,125.3,123.5,117.8,109.6,84.3,73.6,58.6,44.9,34.1,21.5.

[0084] Example 8

[0085] The chiral derivative of the seven-membered indole spiroheterocyclic ring in this embodiment is N-((2'R, 3S, Z)-1-allyl-2'-(naphthalen-2-yl)-6'-phenyl-4', 7'-dihydro-2'-hydrospiro[indole-3,3'-oxacyclohexane]-2-ethylidene)-4-methylbenzenesulfonamide (carbonate and naphthalen-2-yl indole are used in the synthesis of the substrate (indole is used in all other embodiments not described here))

[0086]

[0087] White solid, yield 58%, er 99:1, dr>95:5;

[0088] 1 H NMR (600MHz, CDCl3) δ (ppm): 8.03 (d, J = 8.4Hz, 2H), 7.84 (d, J = 7.2Hz, 1H), 7.62 (d, J = 7.8Hz, 1H), 7.49 (d, J = 8.4Hz, 3H), 7.46 (d, J =7.2Hz,1H),7.43–7.41(m,2H),7.39–7.31(m,6H),7.20(t,J=7.2Hz,1H),7.11(t,J=6.6Hz,1H),6.88(d,J=9.0Hz,1H),6.50(d,J =7.8Hz,1H),6.31(s,1H),6.22–6.20(m,1H),5.11(d,J=14.4Hz,1H),5.04(d,J=15.0Hz,1H),4.82–4.76(m,1H),4.34(d,J=10.2H z,1H),4.31–4.24(m,2H),4.20(dd,J=15.0,4.2Hz,1H),3.86(dd,J=16.2,6.0Hz,1H),2.75(dd,J=15.0,8.4Hz,1H),2.48(s,3H).

[0089] 13C NMR (151MHz, CDCl3) δ (ppm): 167.5, 144.7, 142.5, 142.3, 141.3, 141.2, 135.7, 132.8, 132.5, 131.0, 129.4, 129.3, 128.7, 128.2, 128.1, 127.9,127.4,127.2,126.9,126.5,126.3,126.2,126.1,125.7,125.6,124.6,123.2,117.5,109.4,87.8,73.6,58.9,44.9,34.2,21.5.

[0090] Example 9

[0091] The chiral derivative of the seven-membered indole spiroheterocyclic ring in this embodiment is N-((2'R, 3S, Z)-1-allyl-6'-(4-fluorophenyl)-2'-phenyl-4', 7'-dihydro-2'-hydrospiro[indole-3,3'-oxacyclohexane]-2-ethylidene)-4-methylbenzenesulfonamide (4-fluorocarbonate is used when synthesizing the substrate)

[0092]

[0093] White solid, yield 52%, er 93:7, dr>95:5;

[0094] 1 H NMR (600MHz, CDCl3) δ (ppm): 7.96 (d, J = 8.4Hz, 2H), 7.72 (d, J = 7.8Hz, 1H), 7.43–7.40 (m, 2H), 7.32 (d, J = 8.4Hz, 2H), 7.22 (t, J = 8.4Hz,1H),7.10–7.07(m,3H),7.06–7.03(m,1H),6.98–6.95(m,2H),6.90(d,J=7.8Hz,2H),6.61(d,J=7.8Hz,1H),6.13–6.11(m ,1H),6.08(s,1H),5.19–5.12(m,1H),5.01(d,J=15.0Hz,1H),4.96(d,J=14.4Hz,1H),4.89(d,J=10.2Hz,1H),4.56(d,J=17.4Hz ,1H),4.45–4.41(m,1H),4.09(dd,J=15.6,4.8Hz,1H),4.01(dd,J=15.6,5.4Hz,1H),2.70(dd,J=15.0,8.4Hz,1H),2.46(s,3H).

[0095] 13C NMR (151MHz, CDCl3) δ (ppm): 167.5, 162.4 (CF, 1 J C–F =247.2Hz),143.6,142.5,142.3,141.2,138.2,137.2(CF, 3 J C–F =2.9Hz),131.0,129.9,129.3,128.2,127.73,127.68,127.6,127.3,127.0,126.8,126.2,123.2,117.8,115.5(CF, 2 J C–F =21.6Hz),109.5,87.8,73.5,58.8,45.1,34.1,21.5.

[0096] Example 10

[0097] The chiral derivative of the seven-membered indole spiroheterocyclic ring in this embodiment is N-((2'R, 3S, Z)-1-allyl-2'-phenyl-6'-(p-tolyl)-4',7'-dihydro-2'-hydrospiro[indole-3,3'-oxacyclohexane]-2-ethylidene)-4-methylbenzenesulfonamide (4-methyl carbonate was used when synthesizing the substrate)

[0098]

[0099] White solid, yield 61%, er 97:3, dr>95:5;

[0100] 1H NMR (600MHz, CDCl3) δ (ppm): 7.99 (d, J = 8.4Hz, 2H), 7.77 (d, J = 7.8Hz, 1H), 7.39 (d, J = 7.2Hz, 2H), 7.33 (d, J = 7.8Hz, 2H), 7.24–7. 21(m,3H),7.09–7.05(m,2H),6.99–6.97(m,2H),6.93(d,J=7.8Hz,2H),6.62(d,J=7.8Hz,1H),6.16–6.16(m,1H),6.10(s,1H),5. 21–5.14(m,1H),5.07(d,J=14.4Hz,1H),4.98(d,J=15.6Hz,1H),4.90(d,J=10.2Hz,1H),4.57(d,J=17.4Hz,1H),4.45(dd,J=16.2 ,3.0Hz,1H),4.13(dd,J=14.4,3.6Hz,1H),4.03(dd,J=15.6,4.8Hz,1H),2.70(dd,J=15.0,9.0Hz,1H),2.46(s,3H),2.41(s,3H).

[0101] 13 C NMR (151MHz, CDCl3) δ (ppm): 167.5, 144.4, 142.5, 142.1, 141.3, 138.3, 138.2, 137.2, 131.0, 129.9, 129.3, 129.2, 12 8.1,127.8,127.6,127.2,127.0,126.1,126.0,125.9,123.2,117.8,109.4,87.9,73.5,58.7,45.1,34.1,21.5,21.1.

[0102] Embodiment 11

[0103] The chiral derivative of the seven-membered indole spiroheterocyclic ring in this embodiment is N-((2'R, 3S, Z)-1-allyl-6'-(3-fluorophenyl)-2'-phenyl-4',7'-dihydro-2'-hydrospiro[indole-3,3'-oxacyclohexane]-2-ethylidene)-4-methylbenzenesulfonamide (3-fluorocarbonate is used when synthesizing the substrate)

[0104]

[0105] White solid, yield 47%, er 95:5, dr>95:5;

[0106] 11H NMR (600 MHz, CDCl3) δ (ppm): 7.96 (d, J = 7.2 Hz, 2H), 7.70 (d, J = 7.8 Hz, 1H), 7.38–7.32 (m, 3H), 7.23–7.21 (m, 2H), 7.15 (d, J = 9.6 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 7.06–7.01 (m, 2H), 6.98–6.95 (m, 2H), 6.90 (d, J = 7.2 Hz, 2H), 6.61 (d, J = 7.2 Hz, 1H), 6.21 (s, 1H), 6.08 (s, 1H), 5.19–5.13 (m, 1H), 5.01 (d, J = 15.0 Hz, 1H), 4.96 (d, J = 14.4 Hz, 1H), 4.89 (d, J = 10.8 Hz, 1H), 4.56 (d, J = 17.4 Hz, 1H), 4.44 (d, J = 15.6 Hz, 1H), 4.11 (dd, J = 15.0, 4.2 Hz, 1H), 4.01 (dd, J = 15.6, 4.8 Hz, 1H), 2.71 (dd, J = 15.0, 9.0 Hz, 1H), 2.45 (s, 3H).

[0107] 13 13C NMR (151 MHz, CDCl3) δ (ppm): 167.4, 163.0 (C-F, 1 J C–F = 245.8 Hz), 143.5, 143.3 (C-F, 3 J C–F = 7.2 Hz), 142.5, 142.3, 141.2, 138.1, 131.0, 130.1 (C-F, 3 J C–F = 8.6 Hz), 129.9, 129.3, 128.3, 128.0, 127.7, 127.6, 127.3, 127.0, 126.2, 123.3, 121.7, 117.9, 114.3 (C-F, 2 J C–F = 21.7 Hz), 113.0 (C-F, 2 J C–F = 21.7 Hz), 109.5, 87.8, 73.2, 58.8, 45.2, 34.1, 21.5.

[0108] Example 12

[0109] The chiral derivative of the seven-membered indole spiroheterocyclic ring in this embodiment is N-((2'R, 3S, Z)-1-allyl-2'-phenyl-6'-(3-methylphenyl)-4',7'-dihydro-2'-hydrospiro[indole-3,3'-oxacyclohexane]-2-ethylidene)-4-methylbenzenesulfonamide (3-methyl carbonate was used in the synthesis of the substrate)

[0110]

[0111] White solid, yield 61%, er 95:5, dr>95:5;

[0112] 1 H NMR (600MHz, CDCl3) δ (ppm): 7.99 (d, J = 8.4Hz, 2H), 7.78 (d, J = 7.2Hz, 1H), 7.34–7.28 (m, 5H), 7.23 (t, J = 7.2Hz, 1H), 7.17 (d, J =6.6Hz,1H),7.10–7.05(m,2H),6.99–6.97(m,2H),6.93(d,J=7.2Hz,2H),6.62(d,J=8.4Hz,1H),6.19–6.17(m,1H),6.11(s,1H ),5.20–5.14(m,1H),5.06(d,J=14.4Hz,1H),4.98(d,J=15.0Hz,1H),4.89(d,J=10.2Hz,1H),4.57(d,J=17.4Hz,1H),4.47–4. 43(m,1H),4.15(dd,J=15.0,4.2Hz,1H),4.02(dd,J=16.2,6.0Hz,1H),2.70(dd,J=15.0,8.4Hz,1H),2.46(s,3H),2.43(s,3H).

[0113] 13 C NMR (151MHz, CDCl3) δ (ppm): 167.5, 144.7, 142.5, 142.2, 141.3, 141.1, 138.3, 138.2, 131.0, 129.9, 129.2, 128.5, 128 .2,128.1,127.8,127.6,127.2,127.0,126.8,126.6,126.1,123.2,117.8,109.4,87.9,73.5,58.7,45.1,34.2,21.5.

[0114] Embodiment 13

[0115] The seven-membered indole spiroheterocyclic chiral derivative of this embodiment is N-((2'R, 3S, Z)-1-allyl-6'-(naphthalen-2-yl)-2'-phenyl-4',7'-dihydro-2'-hydrospiro[indole-3,3'-oxacyclohexane]-2-ethylidene)-4-methylbenzenesulfonamide (naphthalen-2-yl carbonate was used in the synthesis of the substrate)

[0116]

[0117] White solid, yield 52%, er 95:5, dr>95:5;

[0118] 1 H NMR (600MHz, CDCl3) δ (ppm): 7.98 (d, J = 8.4Hz, 2H), 7.93 (s, 1H), 7.89–7.85 (m, 3H), 7.77 (d, J = 7.8Hz, 1H), 7.62 (d, J = 8.4Hz, 1H), 7 .53–7.48(m,2H),7.31(d,J=7.2Hz,2H),7.21(t,J=7.8Hz,1H),7.07–7.04(m,2H),6.99–6.97(m,2H),6.93(d,J=7.2Hz,2H),6.61( d,J=8.4Hz,1H),6.33–6.31(m,1H),6.13(s,1H),5.22–5.15(m,2H),5.07(d,J=15.0Hz,1H),4.89(d,J=10.2Hz,1H),4.57(d,J=16. 8Hz,1H),4.47–4.43(m,1H),4.18(dd,J=15.0,4.8Hz,1H),4.02(dd,J=16.8,5.4Hz,1H),2.75(dd,J=15.0,8.4Hz,1H),2.44(s,3H).

[0119] 13 C NMR (151MHz, CDCl3) δ (ppm): 167.4, 144.7, 142.5, 142.3, 141.3, 141.2, 135.7, 132.8, 132.5, 131.0, 129.4, 129.3, 128.6, 128.2, 128.1, 127.9,127.4,127.2,126.9,126.5,126.3,126.2,126.1,125.7,125.6,124.6,123.2,117.5,109.4,87.8,73.6,58.9,44.9,34.2,21.5.

[0120] Embodiment 14

[0121] The seven-membered indole spiroheterocyclic chiral derivative of this embodiment is N-((2'R, 3S, Z)-1-allyl-2'-phenyl-6'-(thiophen-2-yl)-4', 7'-dihydro-2'-hydrospiro[indole-3,3'-oxacyclohexane]-2-ethylidene)-4-methylbenzenesulfonamide (thiophen-2-yl carbonate was used in the synthesis of the substrate).

[0122]

[0123] White solid, yield 76%, er 97:3, dr>95:5;

[0124] 1 H NMR (600MHz, CDCl3) δ (ppm): 7.95 (d, J = 8.4Hz, 2H), 7.74 (d, J = 6.6Hz, 1H), 7.30 (d, J = 7.8Hz, 2H), 7.24 (d, J = 6.6Hz, 1H), 7.21 (t, J =7.8Hz,1H),7.11(d,J=3.0Hz,1H),7.09–7.03(m,3H),6.97–6.94(m,2H),6.89(d,J=7.8Hz,2H),6.60(d,J=8.4Hz,1H),6.35–6.3 2(m,1H),6.04(s,1H),5.19–5.14(m,1H),5.11(d,J=14.4Hz,1H),4.93(d,J=15.6Hz,1H),4.88(d,J=10.2Hz,1H),4.56(d,J=16.8 Hz,1H),4.46–4.42(m,1H),4.08(dd,J=15.6,4.8Hz,1H),4.01(dd,J=16.2,6.0Hz,1H),2.67(dd,J=15.6,8.4Hz,1H),2.44(s,3H).

[0125] 13 C NMR (151MHz, CDCl3) δ (ppm): 167.3, 144.1, 142.5, 142.2, 141.2, 138.1, 138.0, 130.9, 129.9, 129.2, 128.2, 127.8, 1 27.77,127.75,127.3,126.9,126.1,124.8,124.7,123.3,123.2,117.8,109.5,87.9,72.9,58.9,45.2,34.1,21.5.

[0126] Embodiment 15

[0127] The seven-membered indole spiroheterocyclic chiral derivative of this embodiment is N-((2'R, 3S, Z)-1-allyl-2', 6'-diphenyl-4', 7'-dihydro-2'H-spiro[indole-3, 3'-oxacyclohexane]-2-ethylidene)-4-methylbenzenesulfonamide, and the structure is shown in 3a. The seven-membered indole spiroheterocyclic chiral derivative can undergo double bond epoxidation reaction under certain conditions to generate its double bond epoxidation product 4, and the reaction formula is:

[0128]

[0129] The specific preparation steps are as follows:

[0130] To a solution of 3a (0.1 mmol) in dichloromethane (2.0 mL) was added m-CPBA (0.3 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by thin layer chromatography. After the reaction was completed, the reaction was quenched with a saturated NaHCO solution and extracted with dichloromethane. The combined organic phases were collected and dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=30 / 1-10 / 1) to separate the product 4, which was the double bond epoxidation product. The double bond epoxidation reaction formula is:

[0131]

[0132] N-((4R,Z)-1'-allyl-4,7-diphenyl-5,8-dioxaspiro[bicyclo[5.1.0]octane-3,3'-indol]-2'-ethylidene)-4-methylbenzenesulfonamide

[0133]

[0134] White solid, yield 60%, er 96:4;

[0135] 1H NMR (600MHz, CDCl3) δ (ppm): 7.96 (d, J = 8.4Hz, 2H), 7.69 (d, J = 8.4Hz, 2H), 7.52–7.47 (m, 3H), 7.42 (t, J = 7.8Hz, 1H), 7.35 (d, J = 8.4Hz, 2 H),7.16(t,J=7.2Hz,1H),7.07(t,J=7.8Hz,1H),7.00–6.97(m,2H),6.93(d,J=7.2Hz,2H),6.87(t,J=7.8Hz,1H),6.58(d,J=8.4Hz,1H), 5.95(s,1H),5.19–5.12(m,1H),5.07(d,J=13.8Hz,1H),4.89(d,J=10.2Hz,1H),4.57(d,J=17.4Hz,1H),4.42–4.38(m,1H),4.26(d,J=13 .8Hz,1H),4.01(dd,J=16.2,6.0Hz,1H),3.54(dd,J=14.4,7.2Hz,1H),3.12(t,J=6.6Hz,1H),2.61(dd,J=15.0,6.6Hz,1H),2.46(s,3H).

[0136] 13 C NMR (151MHz, CDCl3) δ (ppm): 166.2, 142.6, 142.4, 141.0, 139.5, 137.1, 129.8, 129.3, 129.0, 128.8, 128.5, 128.1 ,127.9,127.3,127.1,126.5,126.3,125.1,123.3,118.0,110.0,89.5,77.9,63.2,62.6,60.3,45.3,35.9,21.5.

[0137] The beneficial effects of the present invention are specifically described below through test examples.

[0138] Antibacterial activity test of seven-membered indole spiroheterocyclic chiral derivatives:

[0139] (1) Experimental purpose:

[0140] The agar plate two-fold dilution method was used to determine the effects of the tested compounds (compounds 3b, 3j, 3m, and 4) on clinically isolated pathogenic bacteria (including sensitive Escherichia coli (E. - ), enzyme-producing Escherichia coli (large E + ), sensitive Klebsiella pneumoniae (E - ), enzyme-producing Klebsiella pneumoniae (E +), sensitive Staphylococcus aureus (MSSA), drug-resistant surface Staphylococcus aureus (MRSE), sensitive surface Staphylococcus aureus (MSSE), drug-resistant Staphylococcus aureus (MRSA), Escherichia coli standard strain (ATCC25922) and Staphylococcus aureus standard strain (ATCC29213, each type of strain is about 1-3 strains, a total of about 24 strains) MIC values.

[0141] 1.(2) Experimental basis:

[0142] The minimum inhibitory concentration (MIC) was determined using the agar two-fold dilution method recommended by the Clinical and Laboratory Standards Institute (CLSI).

[0143] (3) Experimental methods:

[0144] Add 1mL of the test drug solution to a sterile plate, then add 14mL of melted 50℃ MHA medium, mix well, and make the final drug concentration in each plate be 128, 64, 32, 16, 8μg / mL, respectively; after cooling, inoculate bacteria with a multi-point inoculator, the inoculation amount is about 104CFU / mL, cover the plate, place it in an incubator, 36±1℃, incubate for 20-24h. After the incubation, observe with the naked eye, and the lowest sample concentration in the plate where no bacteria grow is its minimum inhibitory concentration (MIC). At the same time, set up a blank bacteria control without any sample.

[0145] (4) Experimental results: The MIC value of compounds 3b, 3j, 3m, 4, etc. against the standard strain of Escherichia coli (ATCC25922) was 128 μg / mL, showing activity against it.

[0146] The compound prepared by the present invention can effectively inhibit the standard strain of Escherichia coli (ATCC25922) and has good antibacterial activity. Other compounds also have antibacterial effects, and the experimental methods and final effects are the same. In order to reduce repetitive content, the experimental contents of other compounds are no longer listed one by one.

[0147] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, based on the above content of the present invention, according to the common technical knowledge and customary means in the art, other various forms of modification, replacement or change can be made without departing from the above basic technical ideas of the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A seven-membered indole spiroheterocyclic chiral derivative constructed by palladium catalysis, characterized in that: The general structural formula of the chiral derivative is: Among them, R 1 It is one of phenyl, halogen-substituted phenyl and naphthyl; R 2 It is one of phenyl, halogen-substituted phenyl and naphthyl.

2. The structure of the seven-membered indole spiroheterocyclic chiral derivative is selected from the following:

3. The method for preparing a seven-membered indole spiroheterocyclic chiral derivative constructed by palladium catalysis as claimed in claim 1, characterized in that: The following steps are involved: Add 5 mol% eqPd2(dba)3 to a 25 mL sealed tube dried in a glove box. . CHCl3 and 15 mol%eq chiral ligand L2, seal the lid, take out from the glove box, add 2mL dry mesitylene under argon atmosphere, and stir the resulting suspension at 60°C for 30 minutes for coordination, then cool the reactant to room temperature, add 1.0eq azadiene substrate 1 and 2.0eq vinyl cyclic carbonate substrate 2 under argon atmosphere, stir the reaction mixture at room temperature for 2 hours, then transfer it to 100°C and stir for 3h, the reaction is completed by thin layer chromatography monitoring, and then directly purify the reaction mixture by column chromatography to obtain the corresponding target product 3, which is the chiral derivative, and the reaction formula is:

4. The preparation method according to claim 3, characterized in that: The azadiene substrate 1 has R 1 is phenyl, the azadiene substrate 1 is substrate 1a, and the preparation method thereof comprises the following steps: Step 1: Weigh 9.53 g of indole into a round-bottom flask, add 10.85 mL of TsN3, react at 60 °C for 14 h under condensation reflux conditions, the color changes to a dark red-brown liquid accompanied by solids, add a small amount of anhydrous methanol and stir until solids precipitate, filter and dry, and weigh to obtain a pink solid I; Step 2: Weigh 1.2 g of I and add it to a washed round-bottom flask covered with a rubber stopper. Add 4 mL of dry dichloromethane, 0.65 mL of benzaldehyde, and 1.3 mL of BF3·Et2O in sequence under argon. React at room temperature under argon atmosphere. After 1 h, it turns into a yellow solid. Add a small amount of anhydrous methanol and sonicate until solid particles precipitate. Filter and dry to obtain a light yellow solid II. Step 3: Weigh 0.1eq Pd(OAc)2 and 0.15eq ligand L1 into a sealed tube, add 10mL dry dichloromethane under argon atmosphere, react at 40°C for 30min, and the coordination is successful when the color changes from red to yellow; then add 1eq II, 3eq allyl bromide, and 2eq potassium tert-butoxide into the sealed tube under argon atmosphere, react at 40°C for 2h, monitor the reaction with thin layer chromatography, use petroleum ether / ethyl acetate system as the developing solvent, and the ratio of petroleum ether to ethyl acetate is 6:

1. After the reaction is completed, concentrate and dry under reduced pressure, purify by column chromatography, use petroleum ether:ethyl acetate = 10:1 as the eluent, and use 300mL dichloromethane to obtain the azadiene substrate 1a; The reaction formula for preparing azadiene substrate 1a is:

5. A method for preparing a seven-membered indole spiroheterocyclic chiral compound 4, characterized in that: m-CPBA was added to a dichloromethane solution of 3a at room temperature, and the reaction mixture was stirred at room temperature for 12 hours. The reaction was monitored by thin layer chromatography. After the reaction was completed, the reaction was quenched with a saturated NaHCO3 solution and extracted with dichloromethane. The combined organic phases were collected and dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether / ethyl acetate = 30 / 1-10 / 1 to obtain the product 4:

6. Use of the seven-membered indole spiroheterocyclic chiral derivative constructed by palladium catalysis as claimed in claim 1 or 2 in the preparation of anti-Escherichia coli drugs; or use of the product 4 obtained as claimed in claim 5 in the preparation of anti-Escherichia coli drugs.

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